ANPEP

Chr 15

alanyl aminopeptidase, membrane

Also known as: AP-M, AP-N, APN, CD13, GP150, LAP1, P150, PEPN

NCBI Gene: 290 ENSG00000166825 UniProt: P15144 OMIM: 151530

Aminopeptidase N is a zinc metalloprotease that cleaves peptides in the intestinal brush border for final protein digestion and processes various peptide hormones and neuropeptides throughout the body. This gene is not well-constrained against loss-of-function variants and currently has no established Mendelian disease associations in pediatric populations. The protein also serves as a receptor for certain coronaviruses and has been implicated in some hematologic malignancies.

OMIM ResearchSummary from RefSeq, UniProt

Aminopeptidase N is located in the small-intestinal and renal microvillar membrane, and also in other plasma membranes. In the small intestine aminopeptidase N plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Its function in proximal tubular epithelial cells and other cell types is less clear. The large extracellular carboxyterminal domain contains a pentapeptide consensus sequence characteristic of members of the zinc-binding metalloproteinase superfamily. Sequence comparisons with known enzymes of this class showed that CD13 and aminopeptidase N are identical. The latter enzyme was thought to be involved in the metabolism of regulatory peptides by diverse cell types, including small intestinal and renal tubular epithelial cells, macrophages, granulocytes, and synaptic membranes from the CNS. This membrane-bound zinc metalloprotease is known to serve as a receptor for the HCoV-229E alphacoronavirus as well as other non-human coronaviruses. This gene has also been shown to promote angiogenesis, tumor growth, and metastasis and defects in this gene are associated with various types of leukemia and lymphoma. [provided by RefSeq, Apr 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.64

Clinical Summary— ANPEP

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

111 VUS of 162 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.000

Z-score 3.64

OE 0.45 (0.32–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.43Z-score

OE missense 0.83 (0.77–0.90)

492 obs / 589.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.32–0.64)

0≤0.351.4

Missense OE?0.83 (0.77–0.90)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 23 / 51.1Missense obs/exp: 492 / 589.8Syn Z: -1.43

This gene — mechanism propensity

0.7034th %ile

GOF

0.78top 25%

LOF

0.1894th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

162 submitted variants in ClinVar

ClinVar

Classification Summary

VUS111

Likely Benign18

Benign11

111

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	111	0	0	111
Likely Benign	12	0	6	18
Benign	1	4	6	11
Total	124	4	12	140

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap ANPEP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →